In the present study we have defined a new syndrome composed of insulin resistance and acanthosis nigricans. We have demonstrated that in some of these patients the decrease in insulin binding to its receptors is due to a circulating autoantibody to the insulin receptor. The antibody specifically blocks insulin receptors in a variety of tissues and acts through the F(ab)2 binding sites. Different patients' antisera produce the decrease in binding via different mechanisms. Thus, these antibodies serve as unique probes of both insulin structure and function.